This research proposal describes a mentored training program for the development of an academic career of a physician scientist. The goal of the proposal is to study glaucoma at the Casey Eye Institute at Oregon Health & Science University (OHSU). As the principal investigator and Assistant Professor at the Casey Eye Institute, Shandiz Tehrani, MD, PhD, will treat patients with glaucoma and also perform research to understand the cellular and molecular effects of how glaucoma results in optic nerve damage and blindness. OHSU provides an exceptional environment for him to further delineate the molecular mechanisms of glaucoma, with the goal of translating the results into novel therapeutics to treat and prevent glaucoma. John Morrison, MD and Elaine Johnson, ScD will serve as his mentors. Dr. Morrison is a Professor of Ophthalmology at OHSU, with clinical and research experience spanning the past 30 years. Dr. Johnson is an Associate Professor of Ophthalmology at OHSU, who has spent over 20 years making significant contributions to the understanding of the molecular changes that occur in glaucomatous optic neuropathy. Glaucoma is the second leading cause of blindness in the United States, resulting from damage to the axons of the optic nerve. While lowering intraocular pressure slows down the progression of glaucoma, it is not a cure. Development of alternative strategies to protect the optic nerve is currently hampered by our limited understanding of the molecular and cellular processes that lead to optic nerve and axon damage in glaucoma. Dr. Tehrani's research will improve this understanding by concentrating on the role that the actin cytoskeleton of the optic nerve head plays in the setting of glaucoma, and test whether this may become a new therapeutic target to prevent and/or control glaucomatous optic nerve damage. The specific hypothesis of this proposal is that the optic nerve actin cytoskeleton, located primarily within astrocyte processes, contributes to axonal support and is in turn important in the morphologic changes of the optic nerve in glaucomatous optic neuropathy. The first specific aim of this grant will elucidate the rol of the cytoskeleton in axonal support in a rat model of glaucoma. Using 2- and 3-dimensional immunofluorescence microscopy, the actin cytoskeleton of the rat optic nerve head will be imaged as a function of optic nerve injury. Dr. Ted Acott, Professor of Ophthalmology at OHSU, has many years' experience studying the cell cytoskeleton with confocal imaging. He will collaborate and help guide Dr. Tehrani's work on these experiments. The second specific aim will focus on characterizing the cytoskeleton of the human optic nerve in glaucoma, using donated tissue meant for research, which will also validate the relevance of the animal glaucoma model to the human disease. Dr. Markus Kuehn at the University of Iowa, who oversees a vast collection of donated human optic nerve tissue, will provide these. The final aim of this grant will determine if pharmacologic modulation of the optic nerve head actin cytoskeleton alters the extent of optic nerve damage in Dr. Morrison's rat model of glaucoma.